Angiotensin II receptor blocking 2,3,6 substituted quinazolinones

ABSTRACT

Novel quinazolinone compounds of the formula: ##STR1## wherein R 5 , R 6 , R 7 , R 8 , R and X are defined in the specification, which have angiotensin II (AII) antagonizing activity, intermediates useful in the preparation of the compounds, methods of producing and using the compounds to alleviate angiotensin induced hypertension and treat congestive heart failure in mammals.

This is a continuation of Ser. No. 07/818,721, filed Jan. 14, 1992, U.S.Pat. 5,290,780, which is a continuation of Ser. No. 07/648,492, filedJan. 30, 1991, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain novel 2, 3, 6 substitutedquinazolinone compounds which have demonstrated enhanced in vivoactivity as angiotensin II (AII) antagonists and are therefore useful inalleviating angiotensin induced hypertension and for treating congestiveheart failure.

2. Description of the Prior Art

The enzyme renin acts on a blood plasma α₂ -globulin, angiotensinogen,to produce angiotensin I, which is then converted by angiotensinconverting enzyme to AII. The substance AII is a powerful vasopressoragent which is implicated as a causative agent for producing high bloodpressure in mammals. Therefore, compounds which inhibit the action ofthe hormone angiotensin II (AII) are useful in alleviating angiotensininduced hypertension.

Furukawa et al., in U.S. Pat. No. 4,340,598, issued Jul. 20, 1982,discloses hypotensive and angiotensin II receptor blocking imidazolederivatives of the formula: ##STR2## wherein R¹ is lower alkyl or phenylC₁₋₂ alkyl optionally substituted with halogen or nitro; R² is loweralkyl, cycloalkyl or phenyl optionally substituted; one of R³ and R⁴ is--(CH₂)_(n) COR⁵ where R⁵ is amino, lower alkoxyl or hydroxyl and n is0, 1, 2 and the other of R³ and R⁴ is hydrogen or halogen; provided thatR¹ is lower alkyl or phenethyl when R³ is hydrogen, n=1 and R⁵ is loweralkoxyl or hydroxyl; and salts thereof.

Furukawa et al., in European Patent Application No. 103,647 discloses4-chloro-2-phenylimidazole-5-acetic acid derivatives useful for treatingedema and hypertension and have angiotensin II receptor blockingactivity of the formula: ##STR3## where R represents lower alkyl andsalts thereof.

D. J. Carini, et al. in published European Patent Applications No.87109919.8, filed Sep. 7, 1987 and No. 89100144.8, filed May 1, 1989disclose angiotensin II receptor blocking imidazoles of the formula:##STR4## wherein the definitions of the substituents may be found withinthe applications.

P. Aldrich et al., in U.S. Pat. No. 4,874,867, issued Oct. 17, 1989,describes tetrazole intermediates of the formula: ##STR5## wherein X²and X¹ are defined therein. These intermediates are described as usefulfor producing compounds which are useful as inhibitors of the hormoneangiotensin II (AII).

D. J. Carini et al., in U.S. Pat. No. 4,880,804, issued Nov. 14, 1989,described substituted benzimidazoles useful as inhibitors of the hormoneangiotensin II (AII) of the formula: ##STR6## wherein R¹ is --CO₂ H,--NHSO₂ CF₃, or ##STR7## R² is H, halogen, NO₂, methoxy, or alkyl of 1to 4 carbon atoms; R³ is alkyl of 1 to 6 carbon atoms, alkenyl oralkynyl of 3 to 6 carbon atoms both of which may be optionallysubstituted with a halogen atom, --OR⁴ or up to two --CO₂ R⁴ ; with theproviso that when R³ is methyl, it must be substituted with --OR⁴ or--CO₂ R₄ ; R⁴ is H, or alkyl of 1-4 carbon atoms; A is H, alkyl of 1 to10 carbon atoms, C_(r) F_(2r+1) where r=1-6, C₆ F₅, halogen, alkoxy of 1to 6 carbon atoms; ##STR8## B is H, alkyl of 1 to 10 carbon atoms, C_(r)F_(2r+1) where r=1-6, C₆ F₅, halogen or alkoxy of 1 to 6 carbon atoms; Xis a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH₂ --.

D. J. Carini et al. in published European Patent Application No.89100142.2, filed May 1, 1989, discloses angiotensin II receptorblocking pyrroles, pyrazoles and triazoles such as: ##STR9##

There has been no teaching or suggestion that the heretofore knownantagonists of AII have the quinazolinone structure.

SUMMARY OF THE INVENTION

According to the present invention, there are provided novel compoundsof Formula I which have enhanced in vivo angiotensin II-antagonizingproperties and are useful as antihypertensives: ##STR10## wherein: R is##STR11## X is straight or branched alkyl of 3 to 5 carbon atoms; n is 1to 3; R⁵ is H;

R⁶ is ##STR12## where R⁹ is H, straight chain lower alkyl of 1 to 4carbon atoms, phenyl, substituted phenyl (substitution selection frommono-lower alkyl of 1 to 3 carbon atoms, --CF₃, nitro, O-alkyl of 1 to 3carbon atoms, NH₂), pyridine, thiophene, or furan;

R¹⁰ is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selection from mono-lower alkyl of 1 to3 carbon atoms, --CF₃, nitro, O-alkyl of 1 to 3 carbon atoms, NH₂),pyridine, thiophene, or furan; provided, however, that R⁹ and R¹⁰ cannotboth be H, R¹¹ is H, straight chain or branched lower alkyl of 1 to 4carbon atoms;

R¹² is straight chain lower alkyl of 1 to 4 carbon atoms, phenyl,substituted phenyl (substitution selection from mono-lower alkyl of 1 to3 carbon atoms, --CF₃, nitro, O-alkyl of 1 to 3 carbon atoms, NH₂),pyridine, thiophene, or furan;

R¹⁷ is straight or branched lower alkyl of 1 to 4 carbon atoms;

R⁷ and R⁸ are H; and pharmaceutically acceptable salts of thesecompounds.

The present invention also provides novel intermediate compounds,methods for making the novel 2, 3, 6 substituted quinazolinoneangiotensin II antagonizing compounds, methods for making the novelintermediates, methods of using the novel quinazolinone angiotensin IIantagonizing compounds to treat hypertension, congestive heart failureand to antagonize the effects of angiotensin II.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts data showing antagonism of the vasopressor response ofAntiotensin II in spontaneously hypertensive rats.

FIGS. 2-7 depict mean average blood pressure response data inaorta-coarcted hypertensive rats.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention are prepared according tothe following reaction schemes.

Referring to Method A, the quinazolinone intermediates of Formula 5, areprepared from the corresponding substituted anthranilic acids 2 whereinthe substituents R⁵, R⁶, R⁷ and R⁸ are described hereinabove except R⁶may not be: ##STR13## The corresponding anthranilic acid 2 is heated toreflux in alkyl acid anhydride 3 wherein X is alkyl of 3 to 5 carbonatoms to provide the 4H-3,1-benzoxazin-4-ones 4 which are isolated byconcentrating the reaction mixtures and used without furtherpurification. When the 4H-3,1-benzoxazin-4-ones 4 are refluxed in ethylalcohol containing ammonia, or ammonium hydroxide solution, thequinazolinone intermediates 5 are obtained. To prepare compounds forwhich R⁶, has been excluded from this method, refer to Schemes I to Xherein. ##STR14##

Referring to Method B, the method of B. Baker, et al., J. Org. Chem. 17,157 (1952) is used to convert the appropriate substituted aniline 6 intoquinazolinone 5 wherein the substituents R⁵, R⁶, R⁷ and R⁸ are describedhereinabove except they may not be as follows: ##STR15## The substitutedaniline 6 is reacted with chloral and hydroxylamine hydrochloride toafford an oxime 7 which is cyclized to the isatin 8 in the presence ofsulfuric acid. The isatin 8 is then hydrolyzed to the anthranilic acid 9using 30% aqueous hydrogen peroxide and aqueous sodium hydroxide.Further reaction as in Method A yields the quinazolinone intermediate 5.To prepare compounds for which R⁶, has been excluded from this method,refer to Schemes I to X herein. ##STR16##

A general reference to the synthesis of 3,4-dihydro-4-oxo-quinazolines 5is given in "The Chemistry of Heterocyclic Compounds, Fused Pyrimidines.Part I: Quinazolines", W. L. F. Armarego; Interscience Publishers(1967), pp. 74-94. Additional references are described in "HeterocyclicCompounds", Vol 6 p. 334 R. C. Elderfield (Editor), Wiley and Sons,1957.

Quinazolinone intermediates 5 are then modified according to thefollowing schemes to obtain the novel 2, 3, 6 substituted quinazolinoneAngiotensin II antagonizing compounds of the present invention.

In Scheme I, 6-methylquinazolinone 10, as prepared by method A, isbrominated with N-bromosuccinimide to give the bromomethyl compound 11.Hydrolysis of the bromide with aqueous potassium carbonate indimethylsulfoxide yields the primary alcohol 12.

The alcohol 12 is oxidized with pyridinium dichromate inN,N-dimethylformamide to afford aldehyde 13. The aldehyde 13 is reactedwith a variety of Grignard Reagents R¹² MgBr or lithium reagents R¹² Liin tetrahydrofuran wherein R¹² is selected from straight or branchedalkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl, pyridyl,thiophene and furan, to give the desired secondary alcohol 14. ##STR17##

In an alternate route to 13, as shown in Scheme II,2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 15, prepared by method Ais reacted via a palladium catalyzed carbonylation to give aldehyde 13.

Ester 16 is formed by palladium (II) catalyzed coupling of2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 15 with carbon monoxideand methanol. Further derivatization of 16 with an excess of GrignardR¹² MgX or R¹² Li affords tertiary alcohol 17 where R¹² is hereinbeforedefined. ##STR18##

The synthetic pathway to tertiary alcohol substituted quinazolinones isshown in Scheme III. ##STR19##

As shown in Scheme III, the palladium (II) catalyzed coupling of(trimethylsilyl)acetylene with2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 15 yields the acetylenicquinazolinone 21. Desilylation of the acetylene with sodium hydroxide inwater-methanol gives the terminal acetylene 22. Hydration with catalyticmercuric sulfate-sulfuric acid in acetic acid affords methyl ketone 23.Reduction of ketone 23 with sodium borohydride in ethanol givessecondary alcohol 24. Alternatively, methyl ketone 23 is reacted withGrignard reagents R¹² MgBr or lithium reagent R¹² Li where R¹² is asdefined before to yield tertiary alcohols 25. The palladium (II)catalyzed coupling of substituted acetylenes where R¹⁷ is defined asstraight or branched lower alkyl of 1 to 4 carbon atoms with2-alkylsubstituted-6-iodo-4(1H)-quinazolinone 15 yields the acetylenicquinazolinone 26. Hydration of 26 with catalytic mercuricsulfate-sulfuric acid in acetic acid gives ketone 27.Reduction of ketone27 with sodium borohydride in ethanol gives secondary alcohol 28.Reaction of ketone 27 with Grignard reagent R¹² MgBr or lithium reagentR¹² Li where R¹² is as defined before yields alcohol 29.

Carboxylic acid 77, prepared by Method A, as presented in Scheme IV, isconverted to the ethyl ester 78 by reaction with ethyl alcoholcontaining a catalytic amount of sulfuric acid. Reduction of 78 withlithium aluminum hydride in tetrahydrofuran affords alcohol 79. Alcohol79 is oxidized with pyridinium dichromate to yield aldehyde 80.##STR20##

Reaction of aldehyde 80 with Grignard reagent R¹² MgBr or lithiumreagent R¹² Li, where R¹² is hereinbefore defined, affords alcohol 81.Also, ethyl ester 78 is reacted with Grignard reagent R¹² MgBr orlithium reagent R¹² Li to give alcohol 82.

The coupling of a quinazolinone intermediate 5 to a biphenyl tetrazole84 where R is as defined before, which are prepared by the methods of P.E. Aldrich et al., U.S. Pat. No. 4,874,867, issued Oct. 17, 1989, isillustrated in Scheme V. ##STR21##

The quinazolinone 5 and the biphenyl 84 are dissolved in acetone oranother suitable solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidinone, methanol, ethanol,t-butanol, tetrahydrofuran, dioxane or dimethylsulfoxide, in thepresence of excess potassium carbonate or another suitable base such assodium carbonate, cesium carbonate, sodium hydride, potassium hydride,sodium methoxide, sodium ethoxide, sodium t-butoxide or potassiumt-butoxide for 2-24 hours, at 20°-60°. The obtained alkylatedquinazolinones 85 may be purified by chromatography or used as is infurther transformations and/or deprotection.

In those cases where the R in the alkylated quinazolinones 85 is atrityl tetrazole, deprotection of the trityl group, as outlined inScheme VI, is accomplished by refluxing an aqueous acetone solution ofthe alkylated quinazolinone 86 with a catalytic amount of hydrochloricacid or other suitable acid such as sulfuric, trifluoroacetic orhydrogen chloride for 2-24 hours. The resulting tetrazoles 87 areisolated by flash chromatography or by trituration with ether andcollection by filtration. ##STR22##

As shown in Scheme VII, alcohol 93 is reacted with an alkylating agentR¹⁷ I, wherein R¹⁷ is alkyl of 1 to 4 carbon atoms, n is 0 to 3 and I isiodide, in the presence of a base, such as sodium hydride, to affordethers 98. The intermediate ethers 98 are deblocked via dilute acid inacetone to give tetrazoles 99. ##STR23##

Alcohol 100, as shown in Scheme VIII, is prepared from 93 by dilute acidhydrolysis to remove the trityl protecting group, is reacted with thedesired acid anhydride, (R¹⁷ CO)₂ O wherein R¹⁷ is defined as straightor branched lower alkyl of 1 to 4 carbon atoms or an acid chloride R¹⁷COCl where n is 0 to 3 in the presence of a base such as pyridine toafford ester 101.

Alcohol 93, is prepared via methods of Schemes I, II and XV.

An alternate synthetic method of preparing 87 from 5 is illustrated inScheme IX. ##STR24##

Quinazolinone 5 is alkylated in a solvent such as acetone in thepresence of potassium carbonate with ##STR25## wherein R⁴⁰ is selectedfrom I, Br or --OSO₂ CF₃ and B is selected from appropriate leavinggroups such as I, Br, Cl, --OMs, --OTs or --OSO₂ CF₃ to give 108.Palladium or nickel catalyzed coupling of 108 with 109 where M can be--MgBr, --Sn(lower alkyl of 1 to 4 carbon atoms or phenyl), Li or --Zncomplex, affords 110 which is deprotected to give 87.

Scheme X illustrates the method of preparing 109. Reaction ofo-bromobenzonitrile with tri-n-butyltin azide affords 111. Furtherreaction of 111 with hydrogen chloride and trityl chloride gives 112.Reaction of 112 with a metal M such as magnesium, or n-BuLi or s-BuLifollowed by ZnCl₂ or (Me)₃ SnCl affords 109. ##STR26##

It will be appreciated that the chemical manipulations of R⁵, R⁶, R⁷ andR⁸ as outlined in Schemes I-X can be accomplished after alkylation asoutlined in Scheme V. Additionally, it will also be appreciated that thechemical manipulations of R⁵, R⁶, R⁷ and R⁸ as outlined in SchemesVII-VIII can be accomplished before alkylation as outlined in Scheme V.The reactions are performed in a solvent appropriate to the reagents andmaterials em-ployed and suitable for the transformation being effected.It is understood by those skilled in the art of organic synthesis thatthe various functionalities present on the molecule must be consistentwith the chemical transformations proposed. This will frequentlynecessitate judgement as to the order of synthetic steps, protectinggroups, if required, and deprotection conditions. Substituents on thestarting materials may be incompatible with some of the reactionconditions. Such restrictions to the substituents which are compatiblewith the reaction conditions will be apparent to one skilled in the art.

Pharmaceutically suitable salts include both the metallic (inorganic)salts and organic salts; a list of which is given in Remington'sPharmaceutical Sciences, 17th Edition, pg. 1418 (1985). It is well knownto one skilled in the art that an appropriate salt form is chosen basedon physical and chemical stability, flowability, hygroscopicity andsolubility. Preferred salts of this invention for the reasons citedabove include potassium, sodium, calcium, magnesium and ammonium salts.

Some of the compounds of the hereinbefore described Schemes have centersof asymmetry. The compounds may, therefore, exist in at least two andoften four stereoisomeric forms. The present invention encompasses allstereoisomers of the compounds whether free from other stereoisomers oradmixed with other stereoisomers in any proportion and thus includes,for instance, racemic mixture of enantiomers as well as thediastereomeric mixture of isomers. The absolute configuration of anycompound may be determined by conventional X-ray cyrstallography.

While the invention has been illustrated using the trityl protectinggroup on the tetrazole, it will be apparent to those skilled in the artthat other nitrogen protecting groups may be utilized. Contemplatedequivalent protecting groups include, benzyl, p-nitrobenzyl,propionitrile or any other protecting group suitable for protecting thetetrazole nitrogen. Additionally, it will be apparent to those skilledin the art that removal of the various nitrogen protecting groups, otherthan trityl, may require methods other than dilute acid.

The compounds of this invention and their preparation can be understoodfurther by the following examples, but should not constitute alimitation thereof.

EXAMPLE 1 2-Butyl-6-(methyl)-4(1H)-quinazolinone

Method A

To 20.0 g of 2-amino-5-methylbenzoic acid is added 60 ml of valericanhydride. The mixture is heated at reflux for 18 hours and thenconcentrated under reduced pressure. The resulting brown solid residueis dissolved in a mixture of 200 ml of 30% of ammonium hydroxidesolution and 300 ml of ethyl alcohol. This mixture is heated at refluxfor 5 hours and then allowed to cool to room temperature. After cooling,the precipitate is collected by filtration. The cake is washed withethanol and water, then dried under vacuum to give 8.92 g of thequinazolone as a white solid.

Method B

The procedure described by B. Baker et. al., J. Org. Chem. 17 157(1952)and Sandmeyer, Helv. Chim. Acta 2, 234(1919) is used.

Examples 2-34 in Table 1 are prepared by using the appropriatelysubstituted anthranilic acids by using synthetic method A or B describedhereinabove.

                  TABLE I                                                         ______________________________________                                         ##STR27##                                                                    Ex.                                 Synthesis                                 No.  R.sup.5                                                                             R.sup.6 R.sup.7                                                                           R.sup.8                                                                           X        Method MP °C.                      ______________________________________                                        2    H     Br      H   H   (CH.sub.2).sub.3 CH.sub.3                                                              A      111                                3    H     H       H   H   (CH.sub.2).sub.3 CH.sub.3                                                              A      129                                4    H     Cl      H   H   (CH.sub.2).sub.3 CH.sub.3                                                              A      194                                5    H     I       H   H   (CH.sub.2).sub.3 CH.sub.3                                                              A      257-258                            6    H     I       H   I   (CH.sub.2).sub.3 CH.sub.3                                                              A      267-268                            7    H     CH.sub.3                                                                              H   H   (CH.sub.2).sub.2 CH.sub.3                                                              A      231-232                            8    H     Cl      H   H   (CH.sub.2).sub.2 CH.sub.3                                                              A      255-256                            9    H     H       H   H   (CH.sub. 2).sub.2 CH.sub.3                                                             A      185-187                            10   H     CH.sub.3                                                                              H   H   (CH.sub.2).sub.3 CH.sub.3                                                              A      *                                  11   H     OCH.sub.3                                                                             H   H   (CH.sub.2).sub.3 CH.sub.3                                                              B      181-182° C.                 12   H     Cl      H   H   (CH.sub.2).sub.2 CH.sub.3                                                              A      194° C.                     ______________________________________                                         *CI MASS SPEC MH.sup.+  217                                              

EXAMPLE 13

2-Butyl-7-carboethoxy-4(1H)-quinazolinone

A mixture of 5.0 g of 2-butyl-7-carboxy-4(1H)-quinazolinone in 100 ml ofabsolute ethanol containing 2 ml of sulfuric acid is refluxed for 48hours. The solvent is evaporated in vacuo and the residue partitionedbetween water and chloroform. The organic layer is washed with aqueoussaturated sodium bicarbonate, dried with anhydrous sodium sulfate,filtered and evaporated to a residue which crystallizes from ethylacetate-hexane to afford 4.5 g of the desired product, mp 145° C.

EXAMPLE 14

2-Butyl-6-(bromomethyl)-4(1H)-quinazolinone

To a suspension of 3.50 g of 6-methylquinazolone in 100 ml of chloroformis added 3.39 g of N-bromosuccinimide and 0.25 g of benzoyl peroxide.The reaction mixture is heated at reflux for 18 hours and then filteredhot. A precipitate of 2.21 g of an inseparable mixture of the desiredbromide and starting 6-methyl quinazolinone is obtained and used in thenext step without further purification.

EXAMPLE 15

2-Butyl-6-(hydroxymethyl)-4(1H)-quinazolinone

To a suspension of 2.0 g of impure2-butyl-6-(bromomethyl)-4(1H)-quinazolinone in 35 ml ofdimethylsulfoxide and 20 ml of water is added 1.0 g of potassiumcarbonate. The reaction mixture is heated at reflux for 6 hours,resulting in a complete solution. Upon cooling slowly to roomtemperature a white precipitate forms and is collected by filtration.The filter cake is purified by flash chromatography on silica gel,eluting with 9:1 chloroform-methanol to give 0.67 g of the desiredproduct as a white solid. CI MASS SPEC 233(M+H).

EXAMPLE 16

2-Butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde

To a solution of 0.3 g of 2-butyl-6-(hydroxymethyl)-4(1H)-quinazolinonein 3.5 ml of dry N,N-dimethylformamide is added 1.7 g of pyridiniumdichromate. The reaction mixture is stirred at room temperature for 16hours and then poured into 125 ml of water. The resulting precipitate isremoved by filtration and the filtrate extracted with 9:1chloroform-methanol. The combined organic extracts are dried overmagnesium sulfate, filtered and concentrated in vacuo and combined withthe precipitate above. The combined solids are purified by flashchromatography on silica gel by eluting with 1:1 ethyl acetate-hexanesto give 0.27 g of the desired product. CI MASS SPEC 231(M+H).

EXAMPLE 17

2-Butyl-6-(1-hydroxyethyl)-4(1H)-quinazolinone

To a solution of 0.60 g of2-butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde in 30 ml of drytetrahydrofuran, cooled to 0° C. is added dropwise, 2.61 ml of a 3.0Msolution of methylmagnesium bromide in diethyl ether. The reaction isstirred at 0° C. for 30 minutes and then quenched with 10 ml of aqueousammonium chloride. After diluting with 10 ml of water, the reactionmixture is extracted with 9:1 chloroform-methanol. The combined extractsare dried with magnesium sulfate, filtered and concentrated to yield0.64 g of the desired product. CI MASS SPEC 247(MH⁺).

EXAMPLE 18

2-Butyl-6-(1-hydroxypropyl)-4(1H)-quinazolinone

To a solution of 0.25 g of2-butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde in 10 ml of drytetrahydrofuran, cooled to 0° C., is added 1 63 ml of 2.0M ethylmagnesium bromide in tetrahydrofuran. The reaction mixture is stirredfor 30 minutes at 0° C. and quenched with 20 ml of saturated ammoniumchloride solution and 20 ml of water. The reaction mixture is extractedwith 9:1 chloroform-methanol, dried over magnesium sulfate, filtered andevaporated in vacuo to give 0.26 g of the desired product. CI MASS SPEC261(MH⁺) .

EXAMPLE 19

2-Butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde

To a solution of 1.0 g of 2-butyl-1,4-dihydro-4-oxo-6-iodo-quinazolineand 0.355 g of tetrakis(triphenylphosphine)palladium in 15 ml oftetrahydrofuran and 5 ml of N,N-dimethylformamide, heated to 55° C.under an atmosphere of carbon monoxide is added a solution of 1.40 g oftri-n-butyltin hydride in 2.5 ml of toluene over 6 hours via a syringepump. After the addition is complete the reaction is allowed to cool toroom temperature, diluted with brine and extracted with chloroform. Thecombined organics are concentrated in vacuo and the resulting residuetriturated with ether. The precipitate is collected by filtration andpurified by flash chromatography on silica gel, eluting with 1:1 ethylacetate-hexanes to give 0.35 g of the desired product, m.p. 242°-244° C.

EXAMPLE 20

2-Butyl-6,[(trimethylsilyl)ethylnyl]-4(1H)-quinazolinone

To a solution of 1.0 g of 2-butyl-1,4-dihydro-4-oxo-6-iodo-quinazolinone0.043 g of bis(triphenylphosphine)palladium (II) chloride and 5.8 mg ofcopper (I) iodide in 5.0 ml of N, N-dimethylformamide and 5.0 ml oftriethylamine is added 0.36 g of (trimethylsilyl)acetylene. Theresulting reaction mixture is heated at 45° C. for 1 hour and them 65°C. for 5 hours. Upon cooling, the reation mixture is concentrated invacuo and the residue is purified by flash chromatography on silica gel,eluting with 1:3 ethyl acetate-hexane to yield 0.75 g of the desiredproduct as a white solid. CI MASS SPEC 299(M⁺).

EXAMPLE 21

2-Butyl-6-[(trimethylsilyl)ethylnyl]-7-fluoro-4-(1H)-quinazolinone

The compound is prepared using the experimental conditions of Example 20starting from 7-fluoro-6-bromo-2-butyl-4(1H)-quinazolinone, m.p 192° C.

EXAMPLE 22

2-Butyl-6-ethylnyl-4(1H)-quinazolinone

To a solution of 0.70 g of2-butyl-6-[(trimethylsilyl)ethynyl]-4(1H)-quinazolinone in 20 ml ofmethanol and 20 ml of tetrahydrofuran is added 10.0 ml of 1.0N sodiumhydroxide solution. The reaction is stirred at room temperature for 2hours and then diluted with 5% hydrochloric acid solution until the pHis 2. The resulting tan precipitate is collected by filtration and driedin vacuo to yield 0.50 g of the desired product. CI MASS SPEC 227(MH⁺).

EXAMPLE 23

6-Acetyl-2-butyl-4(1H)-quinazolinone

To a solution of 1.20 g of 2-butyl-6-ethynyl-4(1H)-quinazolinone in 90ml of acetic acid is added 0.45 g of mercuric sulfate, 0.9 ml of waterand 0.3 ml of sulfuric acid. The reaction mixture is heated at refluxfor 5 hours, cooled to room temperature and quenched with 150 ml ofwater. The resulting mixture is concentrated in vacuo, diluted with 150ml of water and extracted with 6:1 chloroform-methanol. The combinedorganics are dried over magnesium sulfate, filtered and concentrated invacuo. The residue is purified by flash chromatography on silica gel,eluting with 1:1 ethyl acetate-hexanes to give 0.67 g of the desiredproduct as a white solid. CI MASS SPEC 245(M⁺).

EXAMPLE 24

2-Butyl-6-(1-hydroxy-1-methylethyl)-4(1H) -quinazolinone

To a solution of 4.00 g 6-acetyl-2-butyl-4-(1H)-quinazolinone in 250 mlof dry tetrahydrofuran, cooled to 0° C., is added dropwise 16.4 ml of3.0M methylmagnesium bromide in diethyl ether. The reaction is stirredat 0° C. for 0.5 hours and then allowed to warm to room temperaturefollowed by quenching with 100 ml of saturated ammonium chloridesolution. The mixture is diluted with 50 ml of water and extracted withethyl acetate. The combined organic layers are washed with brine, driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo.The residue is purified by flash chromatography on silica gel, elutingwith 100:0.25 chloroform-methanol to give 2.75 g of the desired productas a white solid. CI MASS SPEC 261(MH⁺).

EXAMPLE 25

2-Butyl-6-(1-hydroxyethyl)-4(1H)-quinazolinone

To a suspension of 0.102 g of 6-acetyl-2-butyl-4(1H)quinazolinone in10.0 ml of ethanol is added 0.015 g of sodium borohydride. The reactionmixture is stirred for 1.5 hours at room temperature and then dilutedwith 50 ml of water. The aqueous layer is extracted with 5:1chloroform-methanol and the combined organics dried over magnesiumsulfate, filtered and concentrated in vacuo to yield 0.103 g of thedesired product. CI MASS SPEC 247(MH⁺).

EXAMPLE 26

2 -Butyl-6-ethyl-4(1H) -quinazolinone

To a suspension of 0.278 g of 2-butyl-6-ethynyl-4(1H)quinazolinone in 8ml of pyridine is added 0.080 g of 5% palladium-on-barium sulfate. Thereaction is stirred under a hydrogen atmosphere for 48 hours, filtered,concentrated in vacuo and the residue purified by flash chromatographyon silica gel eluting with ethyl acetate-hexanes to give 0.179 g of thedesired product. CI MASS SPEC 231(MH⁺).

EXAMPLE 27

Methyl 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate

To a solution of 1.00 g of 2-butyl-1,4-dihydro-4-oxo-6-iodoquinazolineand 6.0 ml of triethylamine in 25 ml of methanol and 5 ml ofN,N-dimethylformamide is added 0.275 g ofbis(triphenylphosphine)palladium (II) chloride. The reaction mixture isheated at reflux under an atmosphere of carbon monoxide for 16 hours,then allowed to cool and concentrated in vacuo. The residue is purifiedby flash chromatography on silica gel, eluting with 1:1 ethylacetate-hexanes to give 0.389 g of the desired product as a white solid.CI MASS SPEC 261(MH⁺).

EXAMPLE 28

2-Butyl-6-(1-hydroxy-1-methylethyl)-4(1H)-quinazolinone

To a solution of 0.075 g of methyl2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxylate in 5 ml of drytetrahydrofuran, cooled to 0° C., is added dropwise 0.51 ml of asolution of 3.0M methylmagnesium bromide in diethyl ether. The reactionis stirred at 0° C. for 0.5 hours and then at room temperature for 1hour followed by quenching with 10 ml of saturated ammonium chloridesolution. The resulting reaction mixture is diluted with 10 ml of waterand extracted with ethyl acetate. The combined organics are dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue ispurified by flash chromatography on silica gel, eluting with 100:0.25chloroform-methanol to yield 0.055 g of the desired product as a whitesolid, m.p. 190°-192° C.

EXAMPLE 29

2-Butyl-6-(1-methylethenyl)-4(1H)-quinazolinone

To a suspension of 3.66 g of methyltriphenylphosphonium bromide in 30 mlof dry tetrahydrofuran, cooled to -78° C. is added dropwise 5.9 ml of a1.73M solution of n-butyllithium in hexanes. Following completeaddition, the reaction mixture is allowed to warm to room temperatureand stirred for 15 minutes, until all the phosphonium bromide isdissolved. The reaction mixture is then recooled to -78° C. and asuspension of 6-acetyl-2-butyl-4(1H)-quinazolinone in 15 ml of drytetrahydrofuran is added. The reaction is allowed to warm to roomtemperature and stirred for 24 hours followed by quenching withsaturated ammonium chloride solution. After diluting with 10 ml ofwater, the aqueous layer is extracted with chloroform and the combinedorganics dried over magnesium sulfate, filtered and concentrated invacuo. The residue is purified by flash chromatography on silica gel,eluting with 1:2 ethyl acetate-hexanes to give 0.23 g of the desiredproduct as a white solid. CI MASS SPEC 243(MH⁺ ).

EXAMPLE 30

2-Butyl-6-(hydroxyphenylmethyl)-4(1H)-quinazolinone

To a stirred solution of 2.00 g of2-butyl-1,4-dihydro-4-oxo-6-quinazoline-carboxaldehyde in 100 ml oftetrahydrofuran, cooled at 0° C. is added 13.0 ml of 2.0M phenyllithiumand stirring continued for 1 hour. The cooling is removed and thereaction allowed to reach room temperature followed by an additional 30minutes at room temperature. The reaction is diluted with saturatedammonium chloride solution and extracted with ethyl acetate. The organiclayer is dried, evaporated to a residue, which is purified bychromatography on silica gel by elution with 0.25:100methanol-chloroform to give 0.932 g of the desired product. CI MASS SPEC309(MH⁺).

EXAMPLE 31

2-Butyl-6-(1-hydroxyethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A suspension of 2.50 g of 2-butyl-6-(1-hydroxyethyl)-4(1)-quinazolinone, 6.79 g of5-[4'-(bromomethyl([1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazoleand 4.20 g of anhydrous potassium carbonate in 225 ml of dry acetone isheated at reflux for 16 hours. The reaction mixture is allowed to coolto room temperature, filtered and the filtrate evaporated in vacuo. Theresidue is purified by high pressure liquid chromatography on silica gelby eluting with 1:2 ethyl acetate-hexanes to afford 4.25 g of thedesired product as a white solid, FAB M+H 723.

Examples 32-48 in Table II are prepared under substantially the samealkylation conditions as Example 31 from the appropriately substitutedquinazolinone starting materials.

                                      TABLE II                                    __________________________________________________________________________     ##STR28##                                                                                                FAB Low Resolution                                Ex. No.                                                                            R.sup.5                                                                         R.sup.6   R.sup.7                                                                         R.sup.8                                                                         X      Mass Spectrum                                     __________________________________________________________________________    32   H CH(OH)CH.sub.3                                                                          H H (CH.sub.2).sub.3 CH.sub.3                                                            723(M + H)                                        33   H CH.sub.3  H H (CH.sub.2).sub.3 CH.sub.3                                                            693(M + H)                                        34   H CH.sub.2 CH.sub.3                                                                       H H (CH.sub.2).sub.3 CH.sub.3                                                            707(M + H)                                        35   H CH.sub.2 OH                                                                             H H (CH.sub.2).sub.3 CH.sub.3                                                            709(M + H)                                        36   H H         H H (CH.sub.2).sub.2 CH.sub.3                                                            665(M + H)                                        37   H CH(OH)CH.sub.2 CH.sub.3                                                                 H H (CH.sub.2).sub.3 CH.sub.3                                                            737(M + H)                                        38   H C(CH.sub.3).sub.2 OH                                                                    H H (CH.sub.2).sub.3 CH.sub.3                                                            737(M + H)                                        39   H CH.sub.3  H H (CH.sub.2).sub.2 CH.sub.3                                                            693(M + H)                                        40   H H         H H (CH.sub.2).sub.2 CH.sub.3                                                            665(M + H)                                        41   H CO.sub.2 CH.sub.3                                                                       H H (CH.sub.2).sub.3 CH.sub.3                                                            737(M + H)                                        42   H                                                                                ##STR29##                                                                              H H (CH.sub.2).sub.3 CH.sub.3                                                            721(M + H)                                        43   H CH(OCH.sub.3)CH.sub.3                                                                   H H (CH.sub.2).sub.3 CH.sub.3                                                            737(M + H)                                        44   H CH(OCH.sub.3)C.sub.6 H.sub.5                                                            H H (CH.sub.2).sub.3 CH.sub.3                                                            799(M + H)                                        45   H CH(OH)C.sub.6 H.sub.5                                                                   H H (CH.sub.2).sub.3 CH.sub.3                                                            807(M + Na)                                       46   H CH(OCH.sub.3)C.sub.2 H.sub.5                                                            H H (CH.sub.2).sub.3 CH.sub.3                                                            751(M + H)                                        47   H C(CH.sub.3).sub.2 OCH.sub.3                                                             H H (CH.sub.2).sub.3 CH.sub.3                                                            751(M + H)                                        48   H Cl        H H (CH.sub.2).sub.2 CH.sub.3                                                            609(M + H)                                        __________________________________________________________________________

EXAMPLE 49

2-Butyl-6-(1-hydroxyethyl)-3-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a suspension of 2.00 g of2-butyl-6-(1-hydroxyethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 70 ml of 3:1 acetone-water is added one drop of 5% aqueoushydrochloric acid solution. The mixture is then heated at reflux for 16hours. After cooling, the reaction mixture is concentrated in vacuo andthe residue purified by flash chromatography on silica gel by elutionwith 9:1 chloroform-methanol to afford 0,915 g of the desired product asa white solid, m.p. 146°-147° C.

Examples 50-57 in Table III are prepared under substantially the sameconditions as Example 49 from the appropriately substitutedquinazolinone starting materials.

                                      TABLE III                                   __________________________________________________________________________     ##STR30##                                                                    Ex. No.                                                                            R.sup.5                                                                         R.sup.6   R.sup.7                                                                         R.sup.8                                                                         X      MP °C.                                                                      FAB MS                                       __________________________________________________________________________    50   H H         H H (CH.sub.2).sub.3 CH.sub.3                                                            92                                                51   H C(CH.sub.3).sub.2 OH                                                                    H H (CH.sub.2).sub.3 CH.sub.3                                                            156-158                                           52   H CH(OH)CH.sub.2 CH.sub.3                                                                 H H (CH.sub.2).sub.3 CH.sub.3                                                            138-140                                           53   H CH.sub.2 OH                                                                             H H (CH.sub.2).sub.3 CH.sub.3                                                            126-128                                           54   H CH(OH)C.sub.6 H.sub.5                                                                   H H (CH.sub.2).sub.3 CH.sub.3                                                                 543(M + H)                                   55   H CH(OCH.sub. 3)C.sub.2 H.sub.5                                                           H H (CH.sub.2).sub.3 CH.sub.3                                                                 509(M + H)                                   56   H C(C.sub.6 H.sub.5)OCH.sub.3                                                             H H (CH.sub.2).sub.3 CH.sub.3                                                                 557(M + H)                                   57   H C(CH.sub.3).sub.2 OCH.sub.3                                                             H H (CH.sub.2).sub.3 CH.sub.3                                                                 509(M + H)                                   __________________________________________________________________________

EXAMPLE 58

6-[1-(Acetyloxy)ethyl]-2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 1.00 g of2-butyl-6-(1-hydroxyethyl)-3-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]4-yl]methyl-4(3H)-quinazolinonein 2.0 ml of acetic anhydride at room temperature is added 2 drops ofdry pyridine. The reaction is stirred at room temperature for 16 hoursthen evaporated in vacuo. The residue is purified by flashchromatography on silica gel eluting with 95:5 chloroform-methanol toyield 0.059 g of the desired product as a white solid. FAB MASS SPEC523(M+H).

EXAMPLE 59

2-Butyl-6-(1-methoxyethyl)-4-[[2'-(1H-tetrazol)-5-yl([1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

A mixture of 0.300 g of2-butyl-6-(1-methoxyethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl]-methyl-4(3H)-quinazolinonein 20 ml of 3:1 acetone-water containing 1 drop of 5% hydrochloric acidis heated at reflux for 16 hours and evaporated to a residue. Theresidue is purified on silica gel eluting with 95:5 chloroform-methanolto provide 0.171 g of the product as a white solid, mp 154°-156° C.

EXAMPLE 60

2-Butyl-6-(1-methoxyethyl)-3-[[2'-[1-(triphenylmethyl)-1-H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]-methyl-4(3H)-quinazolinone

To a suspension of 0.044 g of a 60% dispersion of sodium hydride inmineral oil and 0.345 ml of methyl iodide in 5.0 ml of drytetrahydrofuran at room temperature is added 0.400 g of2-butyl-6-(1-hydroxyethyl)-3-[[2'-[1-triphenylmethyl)-1H-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein one portion. The reaction is stirred at room temperature for 18 hoursand then poured onto a pad of silica gel. Elution with 1:3 ethylacetate-hexanes and fractions containing the desired product evaporatedto provide 0.356 g of a white solid. FAB MASS SPEC 737(M+H).

EXAMPLE 61

2-Butyl-6-(1-hydroxy-1-methylethyl)-3-[[2'-(1H-(tetrazol-5-yl )[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone monosodium salt

A mixture of 0.400 g of2-Butyl-6-(1-hydroxy-1-methylethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonemonosodium salt, 10 ml of methanol and 0.810 ml of 1N sodium hydroxideis stirred at room temperature for 1 hour and evaporated in vacuo to aresidue which is triturated with ether, filtered and the cake air driedto give the desired product as a solid. FAB MASS SPEC 517(M+H).

EXAMPLE 62

2-Butyl-6-(hydroxymethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone monosodium salt

Following the procedure of Example 182 and using2-Butyl-6-(1-hydroxy-1-methylethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinoneaffords the product of the Example.

EXAMPLE 63

2-Butyl-6-(1-methoxy-1-methylethyl)-3-[[2'-[[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone

To a suspension of 0.049 g of a 60% oil dispersion of sodium hydride in4.5 ml of THF is added 0.76 ml of methyl iodide followed by 0.45 g of2-butyl-6-(1-hydroxy-1-methylethyl)-3-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone.The reaction mixture is stirred at room temperature for 24 hours andthen an additional 0.05 g of 60% sodium hydride and 0.80 ml of methyliodide are added. The reaction is stirred at room temperature foranother 24 hours and then quenched with saturated ammonium chloridesolution and extracted with ether. The organics are dried over MgSO₄,filtered and concentrated in vacuo. The residue is purified by flashchromatography on silica gel, eluting with 1:5 ethyl acetate/hexanes toprovide 0.397 g of the desired product as a white solid. FAB MASS SPEC751(M+H).

EXAMPLE 64

2-Butyl-6-(1-methoxy-1-methylethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

The product of the Example is prepared using the conditions of Example111 and 0.397 g of2-Butyl-6-(1-methoxy-1-methylethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinoneto give 0.188 g of the desired product as a white solid followingchromatography on silica gel by elution with 50:50:5:0.1 ethylacetate/hexanes/methyl alcohol/acetic acid. FAB MASS SPEC 509(M+H).

EXAMPLE 65

2-Butyl-6-(methoxyphenylmethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-(3H)-quinazolinone

To a solution of 0.398 ml of methyl iodide in 5.0 ml of THF is added0.851 g of 60% sodium hydride followed by 0.500 g of2-butyl-6-(hydroxyphenylmethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone.The reaction mixture is stirred for 16 hours at room temperature, thenquenched with saturated NH₄ Cl solution and extracted with ether. Theorganics are dried over MgSO₄, filtered and concentrated in vacuo. Theresidue is purified by flash chromatography on silica gel, eluting withethyl acetate/hexanes (1:5) to provide 0.434 g of the desired product asa white solid. FAB MASS SPEC 799(M+H).

EXAMPLE 66

2-Butyl-6-(methoxyphenylmethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

The product of the Example is prepared using the conditions of Example49 and 0.413 g of2-Butyl-6-(methoxyphenylmethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-(3H)-quinazolinoneto give 0.192 g of the desired product as a white solid followingchromatography on silica gel by elution with 50:50:5:0.1 ethylacetate/hexanes/methyl alcohol/acetic acid. FAB MASS SPEC 557(M+H).

EXAMPLE 67

2-Butyl-6-(1-methoxypropyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.556 ml of methyl iodide in 5.0 ml of THF is added0.071 g of 60% sodium hydride followed by 0.657 g of2-butyl-6-(1-hydroxypropyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]4(3H)-quinazolinone.The reaction is stirred for 16 hours at room temperature, then quenchedwith saturated NH₄ Cl solution and extracted with ether. The organicsare dried over MgSO₄, filtered and concentrated in vacuo. The residue ispurified by flash chromatography on silica gel, eluting with 1:5 ethylacetate/hexanes to provide 0.59 g of the desired product as a whitesolid. FAB MASS SPEC 751(M+H) .

EXAMPLE 68

2-Butyl-6-(1-methoxypropyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H) -quinazolinone

The product of the Example is prepared using the conditions of Example111 and 0.58 g of2-Butyl-6-(1-methoxypropyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinoneto give 0.326 g of the desired product as a white solid followingchromatography on silica gel by elution with 50:50:5:0.1 ethylacetate/hexanes/methyl alcohol/acetic acid. FAB MASS SPEC 509(M+H).

EXAMPLE 69

1-Amino-3-fluoro-4-bromo-benzoic acid

To a solution of 3.0 g of 4-fluoroanthranilic acid in 250 ml of glacialacetic acid is slowly added a solution of 3.2 g of bromine in 10 ml ofacetic acid. The reaction mixture is stirred at room temperature for 8hours and poured into 500 ml of water. The resulting precipitate isfiltered off and the cake crystallized from methyl alcohol to give 3.4 gof the desired product, m.p. 180°.

EXAMPLE 70

6-Bromo-2-butyl-7-fluoro-4(1H)-quinazolinone

Following the procedure of Example 1 and using 3.0 g of1-amino-3-fluoro-4-bromo-benzoic acid, 100 ml of valeric anhydride and200 ml of ammonium hydroxide affords the product of the Example, m.p.225° C.

EXAMPLE 71

2-Butyl-7-fluoro-6-[(trimethylsilyl)ethynyl]-4(1H)-quinazolinone

Using the procedure of Example 20 and6-bromo-2-butyl-7-fluoro-4(1H)-quinazolinone, the product of the Exampleis obtained, m.p. 192° C.

EXAMPLE 72

2-Butyl-6-ethynyl-7-fluoro-4(1H)-quinazolinone

A mixture of 1.0 g of2-butyl-7-fluoro-6-[(trimethylsilyl)ethynyl]-4(1H)-quinazolinone, 20 mlof 1N sodium hydroxide and 25 ml of methyl alcohol is heated at 60° C.for 5 hours then evaporated in vacuo. The residue is dissolved in 100 mlof water and acidified. The resulting solid is collected and dried toafford 700 mg of the desired product as a yellow solid, m.p. 218° C.

EXAMPLE 73

3-[(4-Bromophenyl)methyl]-2-butyl-6-(1-hydroxy-1-methylethyl)-4(3H)-quinazolinone

To a solution of 1.37 g of2-butyl-6-(1-hydroxy-1-methylethyl)-4(1H)-quinazolinone in 115 ml ofacetone is added 1.58 g of 4-bromobenzyl bromide and 2.18 g of anhydrouspotassium carbonate. The resulting suspension is heated to reflux for 16hours. The reaction mixture is then allowed to cool to room temperature,filtered and the filtrate is concentrated in vacuo. The residue ispurified by HPLC eluting with ethyl acetate/hexanes (1:3) to provide thedesired product.

Examples 74-84 in Table VI are prepared under substantially the samealkylation conditions as Example 73 from the appropriately substitutedquinazolinone starting materials.

                  TABLE VI                                                        ______________________________________                                         ##STR31##                                                                    Ex. No.                                                                              R.sup.5                                                                              R.sup.6       R.sup.7                                                                            R.sup.8                                                                           X                                        ______________________________________                                        74     H      I             H    H   (CH.sub.2).sub.3 CH.sub.3                75     H      CH(OH)CH.sub.3                                                                              H    H   (CH.sub.2).sub.3 CH.sub.3                76     H      CH.sub.3      H    H   (CH.sub.2).sub.3 CH.sub.3                77     H      CH.sub.2 OH   H    H   (CH.sub.2).sub.3 CH.sub.3                78     H      H             H    H   (CH.sub.2).sub.3 CH.sub.3                79     H      CH(OH)CH.sub.2 CH.sub.3                                                                     H    H   (CH.sub.2).sub.3 CH.sub.3                80     H      C(CH.sub.3).sub.2 OH                                                                        H    H   (CH.sub.2).sub.3 CH.sub.3                81     H      CH.sub.3      H    H   (CH.sub.2).sub.3 CH.sub.3                82     H      H             H    H   (CH.sub.2).sub.3 CH.sub.3                83     H      CH(OH)C.sub.6 H.sub.5                                                                       H    H   (CH.sub.2).sub.3 CH.sub.3                84     H      Cl            H    H   (CH.sub.2).sub.3 CH.sub.3                ______________________________________                                    

EXAMPLE 85

3-[(4-Bromophenyl)methyl]-2-butyl-6-(1-methoxy-1-methylethyl)-4(3H)-quinazolinone

To a solution of 0.186 g of 60% sodium hydride and 2.90 ml ofiodomethane in THF at room temperature is added 1.00 g of3-[(4-bromophenyl)methyl]-2-butyl-6-(1-hydroxy-1-methylethyl)-4(3H)-quinazolinone.The reaction mixture is stirred overnight at room temperature and thenquenched with ammonium chloride solution and diluted with water. Theaqueous layer is extracted with ether and the combined organics aredried over MgSO₄, filtered and concentrated in vacuo. The residue ispurified by flash chrmoatography eluting with ethyl acetate/hexanes(1:3) to provide the desired product.

Examples 86-89 in Table VII are prepared under substantially the samealkylation conditions as Example 85 from the appropriately substitutedquinazolinone starting materials.

                  TABLE VII                                                       ______________________________________                                         ##STR32##                                                                    Ex. No.                                                                              R.sup.5                                                                              R.sup.6       R.sup.7                                                                            R.sup.8                                                                           X                                        ______________________________________                                        86     H      CH(OCH.sub.3)CH.sub.3                                                                       H    H   (CH.sub.2).sub.3 CH.sub.3                87     H      CH(OCH.sub.3)C.sub.6 H.sub.5                                                                H    H   (CH.sub.2).sub.3 CH.sub.3                88     H      CH(OCH.sub.3)C.sub.2 H.sub.5                                                                H    H   (CH.sub.2).sub.3 CH.sub.3                89     H      C(CH.sub.3).sub.2 OCH.sub.3                                                                 H    H   (CH.sub.2).sub.3 CH.sub.3                ______________________________________                                    

EXAMPLE 90

2-Butyl-6-(1-methoxy-1-methylethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H-quinazolinone

To a suspension of 0.41 g of magnesium turnings in 50 ml of THF is addeda catalytic amount of iodine followed by 1.00 g of the5-(2-bromophenyl)-1-(triphenylmethyl)-1H-tetrazole in 10 ml of THF. Thereaction mixture is heated to reflux until the Grignard formation isinitiated as indicated by the disappearance of the iodine color. Theremaining 6.94 g of the bromide in 70 ml of THF is then added to thereaction at a rate sufficient to maintain a gentle reflux. The reactionis then stirred at room temperature for 4 hours following the completionof the bromide addition.

To a solution of 4.08 g of the3-[(4-bromophenyl)methyl]-2-butyl-6-(1-methoxy-1-methylethyl)-4(3H)-quinazolinoneand 71 mg of 1,4-bis(diphenylphosphino)butane palladium (II) chloride in100 ml of THF is added the Grignard solution described above and theresulting solution is heated to reflux for 2 hours, following the methodof Kumada (Tet. Letters, 52, 5319 (1981)). After cooling to roomtemperature, the reaction is quenched with water and dilute sodiumhydroxide solution and then extracted with ether. The combined organicsare dried over MgSO₄, filtered and concentrated in vacuo. The residue ispurified by flash chromatography on silica gel eluting with ethylacetate/hexanes (1:3) to provide the desired product.

Examples 91-94 in Table VIII are prepared under substantially the samecoupling conditions as Example 90 from the appropriately substitutedquinazolinone starting materials.

EXAMPLE 95

3-[(4-Bromophenyl)methyl]-2-butyl-6-[1-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-methylethyl]-4(3H)-quinazolinone

To a solution of 1.00 g of 3-[(4-bromophenyl)methyl]-2-butyl-6-(1-hydroxy-1-methylethyl)-4(3H)-quinazolinone in 2.0ml of DMF is added 0.438 g of t-butyldimethylsilyl chloride followed by0.4 g of imidazole. The reaction mixture is stirred at room temperaturefor 18 hours and then diluted with water and extracted with ether. Thecombined ether extracts are dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by flash chromatography eluting withethyl acetate/hexanes (1:5) to provide the desired product as a whitesolid.

Examples 96-100 in Table IX are prepared under substantially the sameconditions as Example 95 from the appropriately substitutedquinazolinone starting materials.

                  TABLE VIII                                                      ______________________________________                                         ##STR33##                                                                    Ex. No.                                                                              R.sup.5                                                                              R.sup.6       R.sup.7                                                                            R.sup.8                                                                           X                                        ______________________________________                                        91     H      CH(OCH.sub.3)CH.sub.3                                                                       H    H   (CH.sub.2).sub.3 CH.sub.3                92     H      CH(OCH.sub.3)C.sub.6 H.sub.5                                                                H    H   (CH.sub.2).sub.3 CH.sub.3                93     H      CH(OCH.sub.3)C.sub.2 H.sub.5                                                                H    H   (CH.sub.2).sub.3 CH.sub.3                94     H      C(CH.sub.3).sub.2 OCH.sub.3                                                                 H    H   (CH.sub.2).sub.3 CH.sub.3                ______________________________________                                    

                  TABLE IX                                                        ______________________________________                                         ##STR34##                                                                    Ex. No.                                                                              R.sup.5                                                                             R.sup.6          R.sup.7                                                                           R.sup.8                                                                           X                                       ______________________________________                                        96     H     CH(OTBDMS)CH.sub.3                                                                             H   H   (CH.sub.2).sub.3 CH.sub.3               97     H     CH.sub.2 OTBDMS  H   H   (CH.sub.2).sub.3 CH.sub.3               98     H     CH(OTBDMS)CH.sub.2 CH.sub.3                                                                    H   H   (CH.sub.2).sub.3 CH.sub.3               99     H     C(CH.sub.3).sub.2 OTBDMS                                                                       H   H   (CH.sub.2).sub.3 CH.sub.3               100    H     CH(OTBDMS)C.sub.6 H.sub.5                                                                      H   H   (CH.sub.2).sub.3 CH.sub.3               ______________________________________                                         *TBDMS = tbutyldimethylsilyl                                             

EXAMPLE 101

2-Butyl-6-[1-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-methylethyl]-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a suspension of 0.41 g of magnesium turnings in 50 ml of THF is addeda catalytic amount of iodine followed by 1.00 g of the5-(2-bromophenyl)-1-(triphenylmethyl)-1H-tetrazole in 10 ml of THF. Thereaction mixture is heated to reflux until the Grignard formation isinitiated as indicated by the disappearance of the iodine color. Theremaining 6.94 g of the bromide in 70 ml of THF is then added to thereaction at a rate sufficient to maintain a gentle reflux. The reactionis then stirred at room temperature for 4 hours following the completionof the bromide addition.

To a solution of 5.00 g of 3-[(4-bromophenyl)methyl]-2-butyl-6-[1-[[(1,1-di-methylethyl)dimethylsilyl]oxy]-1-methylethyl]-4(3H)-quinazolinoneand 71 mg of 1,4-bis(diphenylphosphino)butane palladium (II) chloride in100 ml of THF is added the Grignard solution described above and theresulting solution is heated to reflux for 2 hours, fillowing the methodof Kumada (Tet. Letters, 52, 5319 (1981)). After cooling to roomtemperature, the reaction is quenched with water and dilute sodiumhydroxide solution and then extracted with ether. The combined organicsare dried over MgSO₄, filtered and concentrated in vacuo. The residue ispurified by flash chromatography on silica gel eluting with ethylacetate/hexanes (1:3) to provide the desired product.

Examples 102-106 in Table X are prepared under substantially the sameconditions as Example 101 from the appropriately substitutedquinazolinone starting materials.

                  TABLE X                                                         ______________________________________                                         ##STR35##                                                                    Ex. No.                                                                              R.sup.5                                                                             R.sup.6          R.sup.7                                                                           R.sup.8                                                                           X                                       ______________________________________                                        102    H     CH(OTBDMS)CH.sub.3                                                                             H   H   (CH.sub.2).sub.3 CH.sub.3               103    H     CH.sub.2 OTBDMS  H   H   (CH.sub.2).sub.3 CH.sub.3               104    H     CH(OTBDMS)CH.sub.2 CH.sub.3                                                                    H   H   (CH.sub.2).sub.3 CH.sub.3               105    H     C(CH.sub.3).sub.2 OTBDMS                                                                       H   H   (CH.sub.2).sub.3 CH.sub.3               106    H     CH(OTBDMS)C.sub.6 H.sub.5                                                                      H   H   (CH.sub.2).sub.3 CH.sub.3               ______________________________________                                         *TBDMS = tbutyldimethylsilyl                                             

EXAMPLE 107

2-Butyl-6-(1-hydroxy-1-methylethyl)-3-[[2'-[1-triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone

To a solution of 0.50 g of2-butyl-6-[1-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-methylethyl]-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinonein 15.0 ml of THF is added 0.88 ml of a 1.0M solution oftetrabutylammonium fluoride in THF. The reaction is stirred at roomtemperature for 1 hour and then poured into 100 ml of water. The aqueouslayer is extracted with ether and the combined organics are washed withbrine, dried over MgSO₄, filtered and concentrated in vacuo. The residueis purified by flash chromatography on silica gel eluting with ethylacetate/hexanes (1:3) to provide the desired product.

Examples 108-112 in Table XI are prepared under substantially the sameconditions as Example 107 from the appropriately substitutedquinazolinone starting materials.

                  TABLE XI                                                        ______________________________________                                         ##STR36##                                                                    Ex. No.                                                                              R.sup.5                                                                              R.sup.6       R.sup.7                                                                            R.sup.8                                                                           X                                        ______________________________________                                        108    H      CH(OH)CH.sub.3                                                                              H    H   (CH.sub.2).sub.3 CH.sub.3                109    H      CH.sub.2 OH   H    H   (CH.sub.2).sub.3 CH.sub.3                110    H      CH(OH)CH.sub.2 CH.sub.3                                                                     H    H   (CH.sub.2).sub.3 CH.sub.3                111    H      C(CH.sub.3).sub.2 OH                                                                        H    H   (CH.sub.2).sub.3 CH.sub.3                112    H      CH(OH)C.sub.6 H.sub.5                                                                       H    H   (CH.sub.2).sub.3 CH.sub.3                ______________________________________                                    

EXAMPLE 113

5-(2-Bromophenyl)-1-(trimethylstannyl)-1H-tetrazole

To a solution of 1.50 g of o-bromobenzonitrile in 8.0 ml of toluene isadded 1.70 g of trimethyltin azide. The reaction mixture is heated toreflux for 18 hours and then allowed to cool to room temperature. Theresulting white precipitate is isolated by filtration and used withoutpurification in the next step.

EXAMPLE 114

5-(2-Bromophenyl)-1H-tetrazole

To a solution of 1.0 g of5-(2-bromophenyl)-1-(trimethylstannyl)-1H-tetrazole in toluene/THF(10:1) at room temperature is added HCl gas, via a bubbler. Gas additionis continued for 5 minutes after the appearance of a precipitate and thesolid is then isolated by filtration and washed with hexanes.

EXAMPLE 115

5-(2-Bromophenyl)-1-(triphenylmethyl)-1H-tetrazole

To a solution of 0.50 g of 5-(2-bromophenyl)-1H-tetrazole in 20 ml ofCH₂ Cl₂ is added 0.65 g of triphenylmethyl chloride followed by 0.37 mlof triethylamine. The solution is refluxed for 2.5 hours, cooled to roomtemperature and then washed with water, dried over MgSO₄ andconcentrated in vacuo. The residue is purified by flash chromatographyeluting with ethyl acetate/hexanes (1:5) to provide the desired product.

EXAMPLE 116

2-butyl-6-(1-methoxy-1-methylethyl)-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone,sodium salt.

To a solution of 2.488 g of the free tetrazole from Example 57 in 60 mlof methanol is added 5.036 ml of 1.0N sodium hydroxide solution. Themixture is stirred at room temperature for 1 hour and then concentratedin vacuo. The residue is titrated with hexanes, filtered and dried invacuo to provide 2.29 g of the product as a white solid.

EXAMPLE 117

2-Butyl-6-(1-methoxyethyl)-4-[[2'-(1H-tetrazol)-5-yl)[1,1'-biphenyl-4-yl]methyl-4(3H)-quinazolinone, sodium salt.

To a solution of 2.156 g of the free tetrazole from Example 59 in 60 mlof methanol is added 4.359 ml of 1.o N Sodium Hydroxide solution. Themixture is stirred at room temperature for 1 hour and then concentratedin vacuo. The residue is titrated with hexanes, filtered and dried invacuo to provide 2.09 g of the product as a white solid.

EXAMPLE 118

2-Butyl-6-(methoxymethyl)-4-[[2'-(1H-tetrazol)-5-yl)[1,1'-biphenyl]-4-yl]methyl-4(3H)-quinazolinone

To a stirred solution of NaH (500 mg) and primary alcohol from Example53 in dry THF (35 ml) at 0° C., is added CH₃ I (1 ml). The reactionmixture is stirred at room temperature for 4 hours. The reaction mixtureis then carefully poured over crushed ice and extracted with chloroform.The organic layer is washed well with water; dried and concentrated. Thespongy solid obtained is dissolved in acetone (25 ml) and 5N HCL (3 ml)is added. The reaction mixture is stirred at room temperature for 3hours. The reaction mixture is then concentrated and the product ispurified by column chromatography. Yield: 8.5 mg; m.p: 85° C.

UTILITY

The performance of the novel compounds of the present invention areshown in the following In Vitro test. The results of this test forrepresentative compounds of the present invention are shown in Table IV.

ANGIOTENSIN II ANTAGONISTS IN VITRO TESTS

The source of the angiotensin II receptors utilized in the screen isfrom rat adrenocortical microsomes. The cortices are placed in ice coldsucrose buffer (0.2 m sucrose, 1 mm EDTA, 10 mm Trizma base, pH 7.4) andhomogenized in a chilled ground glass tissue grinder. The homogenate iscentrifuged at 3000×g for 10 min. and the resultant supernatant isdecanted through cheesecloth and centrifuged at 12,000×g for 3 min. Theresulting supernatant is then centrifuged at 1000,000×g for 60 min. andthe pellet resuspended in assay buffer (0.25% bovine serum albumin, 5 mmMgCl₂, 50 mm Trizma base, pH 7.2). Binding assays are performed byincubating aliquots of freshly prepared microsomes in the absence orpresence of compound (40 uM final concentration). Ten minutes later, ³H-angiotensin II is added to each tube (2 nM final concentration) andincubated for 60 minutes at 270° C. The reaction is terminated by theaddition of 3 ml of cold assay buffer without albumin and the bound andfree radioactivity is separated rapidly through glass-fiber filtersprewetted with assay buffer. After two additional 3 ml rinses, thefilters are placed in scintillation fluid and counted in a scintillationcounter to determine trapped radioactivity. Compounds that displace 50%of the labelled angiotensin are considered active compounds and are thenevaluated in concentration-response experiments to determine IC₅₀values. The results are shown in Table IV.

                  TABLE IV                                                        ______________________________________                                         ##STR37##                                                                                                              Angio-                                                                        tensin II                                                                     Receptor                            Ex.                                       Binding                             No.  R.sup.5                                                                             R.sup.6       R.sup.7                                                                           R.sup.8                                                                           X        IC.sub.50 (M)                       ______________________________________                                        49   H     CH(OH)CH.sub.3                                                                              H   H   (CH.sub.2).sub.3 CH.sub.3                                                              8.8 ×                                                                   10.sup.-9                           51   H     C(CH.sub.3).sub.2 OH                                                                        H   H   (CH.sub.2).sub.3 CH.sub.3                                                              9.4 ×                                                                   10.sup.-9                           52   H     CH(OH)CH.sub.2 CH.sub.3                                                                     H   H   (CH.sub.2).sub.3 CH.sub.3                                                              1.2 ×                                                                   10.sup.-8                           54   H     (C.sub.6 H.sub.5)CHOH                                                                       H   H   (CH.sub.2).sub.3 CH.sub.3                                                              >1.0 ×                                                                  10.sup.-5                           55   H     CH.sub.3 CH.sub.2 CHOCH.sub.3                                                               H   H   (CH.sub.2).sub.3 CH.sub.3                                                              5.0 ×                                                                   10.sup.-9                           56   H     (C.sub.6 H.sub.5)CHOCH.sub.3                                                                H   H   (CH.sub.2).sub.3 CH.sub.3                                                              8.6 ×                                                                   10.sup.-9                           57   H     (CH.sub.3).sub.2 COCH.sub.3                                                                 H   H   (CH.sub.2).sub.3 CH.sub.3                                                              6.4 ×                                                                   10.sup.-9                           58   H     CH.sub.3 CHOOCCH.sub.3                                                                      H   H   (CH.sub.2).sub.3 CH.sub.3                                                              1.1 ×                                                                   10.sup.-8                           60   H     CH.sub.3 (CH.sub.3 O)CH                                                                     H   H   (CH.sub.2).sub.3 CH.sub.3                                                              8.4 ×                                                                   10.sup.-8                           64   H     (CH.sub.3).sub.2 COCH.sub.3                                                                 H   H   (CH.sub.2).sub.3 CH.sub.3                                                              6.4 ×                                                                   10.sup.-9                           66   H                                                                                    ##STR38##    H   H   (CH.sub.2).sub.3 CH.sub.3                                                              8.6 × 10.sup.-9               68   H                                                                                    ##STR39##    H   H   (CH.sub.2).sub.3 CH.sub.3                                                              5.0 × 10.sup.-9               ______________________________________                                    

The compounds of this invention inhibit the action of AII. Byadministering a compound of this invention to a rat, and thenchallenging with angiotensin II, a blackage of the vasopressor responseis realized. The results of this test on representative compounds ofthis invention are shown in Table V.

AII CHALLENGE

Conscious Male Okamoto-Aoki SHR, 16-20 weeks old, weighing approximately330 g are purchased from Charles River Labs (Wilmington, Mass.).Conscious rats are restrained in a supine position with elastic tape.The area at the base of the tail is locally anesthetized by subcutaneousinfiltration with 2% procaine. The ventral caudal artery and vein areisolated, and a cannula made of polyethylene (PE) 10-20 tubing (fusedtogether by heat) is passed into the lower abdominal aorta and venacava, respectively. The cannula is secured, heparinized (1,000 I.U./ml),sealed and the wound is closed. The animals are placed in plasticrestraining cages in an upright position. The cannula is attached to aStatham P23Db pressure transducer, and pulsatile blood pressure isrecorded to 10-15 minutes with a Gould Brush recorder. (Chan et al.,(Drug Development Res., 18:75-94, 1989).

Angiotensin II (human sequence, Sigma Chem. Co., St. Louis, Mo.) of 0.05and 0.1 ug/kg i.v. is injected into all rats (predosing response). Thena test compound, vehicle or a known angiotensin II antagonist isadministered i.v., i.p. or orally to each set of rats. The two doses ofangiotensin II are given to each rat again at 30, 90 and 150 minutespost dosing the compound or vehicle. The vasopressor response ofangiotensin II is measured for the increase in systolic blood pressurein mmHg. The percentage of antagonism or blockade of the vasopressorresponse of angiotensin II by a compound is calculated using thevasopressor response (increase in systolic blood pressure) ofangiotensin II of each rat predosing the compound as 100%. A compound isconsidered active if at 30 mg/kg i.v. it antagonized at least 50% of theresponse.

The results are shown in Table V and FIG. 1.

                  TABLE V                                                         ______________________________________                                        % INHIBITION (ANGIOTENSIN BLOCKADE) OF                                        ANGIOTENSIN II (AII) VASOPRESSOR RESPONSE                                                                                  Per-                                                             Min.         cent                                  Dose    AII    Con-  Re-   After        Inhibi-                               mg/     Dose   trol  sponse                                                                              Dosing       tion                             Ex.  kg      g/kg   Before                                                                              After Com-         (Aver-                           No.  iv      iv     AII   AII   pound Change age)                             ______________________________________                                                     .05    195   240    0    45                                                   .1     185   240         55                                      49   1       .05    190   217   30    27     40                                            .1     185   225         40     27                               49   1       .05    170   195   45    25     45                                            .1     185   210         25     55                                            .05    170   210   90    40     11                                            .1     185   225         40     27                               49   2       .05    190   200   120   10     78                                            .1     185   220         35     36                                            .05    190   225   150   35     23                                            .1     190   230         40     27                                            .05    175   225   180   50     11                                            .1     175   230   55      0                                                  .05    228   254    0    26                                                   .05    205   235    0    30                                                   0.1    223   272    0    44                                                   0.1    205   250    0    45                                      49           .05    253   253   30     0                                           10      .05    190   190   30     0     100                                           0.1    243   243   30     0                                                   0.1    190   190   30     0     100                                           .05    228   228   90     0                                                   .05    185   185   90     0     100                                           .05    185   230    0    45                                                          185   225         40                                                   .1     180   235         55                                                          185   235         50                                      50   30      .05    175   190   30    15     82                                                   190   190          0                                                   .1     170   195         25     76                                                   190   190          0                                                   .05    170   200   90    30     29                                                   180   215         30                                                   .1     180   210         30     52                                                   185   205         20                                                   .05    170   200   150   30     41                                                   170   190         20                                                   .1     185   220         35     48                                                   170   190         20                                                   .05    220   260    0    40                                                   .05    200   232    0    32                                                   0.1    215   265    0    50                                                   0.1    200   240    0    40                                      51    5*     .05    205   235   30    30                                                   .05    185   210   30    25     30                                            0.1    200   240   30    40                                                   0.1    190   215   30    25     26                                            .05    205   210   90     5                                                   .05    180   193   90    13     75                                            0.1    200   225   90    25                                                   0.1    180   195   90    15     55                                            .05    190   205   150   15                                                   .05    180   190   150   10     63                                            0.1    190   217   150   27                                                   0.1    180   200   150   20     46                                            .05    235   285    0    50                                                   .1     225   285         60                                      *51  1       .05    220   260   30    40     20                                            .1     220   275         55      8                               *51  1       .05    220   245   45    25     50                                            .1     220   260         40     33                                            .05    220   265   90    45     10                                            .1     210   275         65      8                               *51  2       .05    225   250   120   25     50                                *sodium salt                                                             

                 .1     215   265         50     17                                            .05    225   260   150   35     30                                            .1     225   270         45     25                                            .05    225   265   180   40     20                                            .1     235   280         45     25                                            .05    210   265    0    55                                                   .05    205   255    0    50                                                   0.1    215   275    0    60                                                   0.1    210   265    0    55                                      52   5       .05    205   230   30    25                                           oral    .05    190   215   30    25     52                                            0.1    205   240   30    35                                                   0.1    190   220   30    30     43                                            .05    185   205   90    20                                                   .05    185   200   90    15     66                                            0.1    185   205   90    20                                                   0.1    185   206   90    21     63                                            .05    180   195   150   15                                                   .05    175   180   150   15     71                                            0.1    175   201   150   26                                                   0.1    180   200   150   20     60                                            .05    165   220    0    55                                                          185   230         45                                                   .1     175   220         45                                                          190   240         50                                      53   10      .05    155   157   10     2     83                                                   140   155         15                                                   .1     155   165         10     90                                                   130   130          0                                                   .05    155   160   30     5     85                                                   135   145         10                                                   .1     160   165          5     84                                                   155   165         10                                                   .05    160   175   60    15     65                                                   140   160         20                                                   .1     165   180         15     68                                                   150   165         15                                                   .05    200   245    0    45                                                          175   222         47                                                          185   230         45                                                   .1     200   252         47                                                          170   217         55                                                          180   235         55                                      53   10                         30                                                         .05    210   245         35     17                                                   175   215         40                                                          185   225         40                                                   .1     205   250         45     19                                                   175   220         45                                                          195   232         37                                                                      60                                            53           .05    192   237         45     27                                                   170   190         20                                                          175   210         35                                                   .1     195   245         50      4                                                   170   220         50                                                          175   225         50                                                                      90                                                         .05    205   245         40     41                                                   175   195         20                                                          185   207         22                                                   .1     200   250         50     56                                                   175   210         35                                                          177   225         48                                                                      30                                                         .05    207   225         18     76                                                   167   190         23                                                          180   210         30                                                   .1     200   255         55     60                                                   175   197         22                                                          180   223         43                                                                      60                                                         .05    200   240         40     46                                                   170   180         10                                                          200   225         25                                      53           .1     207   250         43     44                                                   170   190         20                                                          190   230         40                                                                      90                                                         .05    195   235         40     35                                                   165   180         15                                                          180   215         35                                                   .1     200   250         50     26                                                   175   190         15                                                          180   230         50                                                   .05    210   275    0    65                                                          230   270         40                                                   .1     210   280         70                                                          235   280         45                                      53   6       .05    200   220   30    20     67                                                   210   225         15                                                   .1     205   220         15     70                                                   210   230         20                                                   .05    205   225   90    20     48                                                   200   235         35                                                   .1     205   240         35     30                                                   205   250         45                                      53   6       .025   235   265    0    30                                                   .05    235   265         30                                                   .1     235   265         30                                      53   6       .025   210   225   30    15     50                                            .05    210   235         25     17                                            .1     215   250         35     17                                            .025   200   210   90    10                                                   .05    190   225         35     17                                            .1     200   235         35     17                                            .05    187   240    0    53                                                          213   260         47                                                   .1     187   240         53                                                          215   265         50                                      53   3       .05    175   205   10    30     62                                                   207   215          8                                                   .1     175   215         40     42                                                   205   225         20                                                   .05    175   210   30    35     45                                                   210   230         20                                                   .1     190   220         30     47                                                   215   235         20                                                   .05    175   215   60    40     30                                                   210   240         30                                                   .1     180   235         55     13                                                   220   255         35                                                   .05    210   270    0    60                                                          225   265         40                                                   .1     205   275         70                                                          235   290         55                                      53   3       .05    200   215   30    15     55                                                   230   260         30                                                   .1     195   215         20     44                                                   220   270         50                                                   .05    200   225   90    25     25                                                   225   275         50                                                   .1     200   235         35     13                                                   225   277         52                                      53   3       .05    175   190   30    15     60                                                   225   250         25                                                   .1     180   210         30     36                                                   225   250         50                                                   .05    200   250    0    50                                                          210   265         55                                                   .1     200   255         55                                                          200   265         65                                      53   3       .05    185   210   30    25     67                                                   190   200         10                                                   .1     185   205         20     67                                                   190   210         20                                                   .05    185   235   90    50     10                                                   195   260         65                                                   .1     190   235         45     17                                                   200   255         55                                                   .025   220   260    0    40                                                          210   255         45                                                   .05    220   265         45                                                          210   260         50                                                   .1     220   275         55                                                          215   265         50                                      53   3       .025   210   225   30    15     53                                                   195   220         25                                      53           .05    207   220         13     65                                                   190   210         20                                                   .1     210   235         25     52                                                   190   215         25                                                   .025   210   230   90    20     47                                                   185   210         25                                                   .05    210   240         30     35                                                   190   222         32                                                   .1     210   250         40                                                          195   235         40     24                                            .05    190   235    0    45                                                          210   255         65                                                   .1     190   245         55                                                          210   255         45                                      54   1       .05    190   215   30    25     47                                                   205   227         32                                                   .1     195   230         35     30                                                   210   245         35                                      54   1       .05    190   207   45    17     75                                                   205   215         10                                                   .1     185   230         45     28                                                   200   227         27                                                   .05    190   217   90    27     49                                                   210   240         30                                                   .1     200   240         40     34                                                   210   235         25                                      54   2       .05    220   220   120    0     85                                                   200   215         15                                                   .1     202   222         20     64                                                   200   215         15                                                   .05    185   205   150   20     67                                                   195   210         15                                                   .1     190   215         25     54                                                   195   215         20                                                   .05    190   207   180   17     69                                                   190   207         17                                                   .1     190   220         30     50                               54   5              190   210         20                                           P.O.*   0.05   210   235   180   25     55                                            0.1    197   245         48     26                                            .05    200   255    0    55                                                   .1     200   255         55                                      55   30      .05    180   190   30    10     82                                            .1     180   195         15     73                                            .05    170   185   90    15     73                                            .1     170   175          5     91                                            .05    185   205   150   20     64                                            .1     190   195          5     91                                            .025   230   260    0    30                                                   .05    225   270         45                                                   .1     235   283         48                                      57   1       .025   205   220   15    15     50                                            .05    220   225          5     89                                            .1     217   242         25     48                                            .025   215   230   30    15     50                                            .05    225   235         10     78                                            .1     225   260         35     27                                            .025   240   245   60     5     83                                            .05    240   255         15     67                                            .1     240   275         35     27                               57   2       .025   230   255   90    25     17                                            .05    225   235         10     78                                            .1     225   255         30     37                                            .025   205   265   120   60     100                                           .05    225   255         30     33                                            .1     235   255         20     58                               57   3       .025   210   225   150   15     50                                            .05    215   230         15     67                                            .1     215   240         25     48                                            .025   207   250    0    43                                                          210   260         50                                                   .05    215   253         38                                                          210   265         55                                                   .1     220   265         45                                                          220   265         45                                      57   *5      .025   205   210   30     5     94                                                   205   205          0                                                   .05    200   207          7     77                                                   200   215         15                                                   .1     198   215         17     64                                                   200   215         15                                                   .025   205   215   60    10     89                                                   195   195          0                                                   .05    215   215          0     87                                                   193   205         12                                                   .1     200   217         17     58                                                   190   210         20                                                   .025   195   200   120    5     94                                                   200   200          0                                                   .05    195   210         15     72                                                   200   210         10                                                   .1     192   220         28     40                                                   200   225         25                                                   .025   195   210   180   15     72                                                   200   210         10                                                   .05    200   215         15     68                                                   200   215         15                                                   .1     200   215         15     56                                                   200   225         25                                                   .025   220   220   240    0     100                                                  190   190          0                                                   .05    195   210         15     62                                                   180   200         20                                                   .1     220   235         15     49                                                   185   215         30                                                   .05    200   260    0    60                                                          210   257         47                                                   .1     205   260         55                                                          200   260         60                                      58   30      .05    195   205   30    10     87                                                   222   225          3                                                   .1     205   205          0     98                                                   205   207          2                                                   .05    190   190   90     0     85                                                   210   225         15                                                   .1     195   195          0     95                                                   210   215          5                                                   .05    180   190   150   10     85                                                   200   205          5                                                   .1     190   207         17     81                                                   205   210          5                                                   .05    235   285    0    50                                                          230   290         60                                                   .1     225   285         60                                                          230   285         55                                      60   1       .05    207   232   30    25     55                                                   215   240         25                                                   .1     215   260         45     17                                                   210   260         50                                      60   1       .05    195   205   45    10     82                                                   215   225         10                                                   .1     190   215         25     43                                                   210   250         40                                                   .05    210   230   90    20     58                                                   210   235         25                                                   .1     215   245         30     43                                                   210   245         35                                      60   2       .05    215   215   120    0     100                                                  220   220          0                                                   .1     210   220         10     86                                                   220   225          5                                                   .05    220   225   150    5     82                                                   205   220         15                                                   .1     215   225         10     52                                                   205   250         45                                                   .05    215   240   180   25     45                                                   210   245         35                                      60           .1     215   250         35     31                                                   205   250         45                                                   .025   195   209    0    14                                                   .025   200   218    0    18                                                   .05    200   215    0    15                                                   .05    195   228    0    33                                                   0.1    200   220    0    20                                                   0.1    200   250    0    50                                      61   2       .025   195   195   30     0                                                   .025   200   200   30     0     100                                           .05    190   190   30     0                                                   .05    180   180   30     0     100                                           0.1    165   165   30     0                                                   0.1    220   220   30     0     100                                           .025   190   190   90     0                                                   .025   197   197   90     0     100                                           .05    185   185   90     0                                                   .05    200   200   90     0     100                                           0.1    185   185   90     0                                                   0.1    205   205   90     0     100                                           .025   150   180   150    0                                                   .025   200   200   150    0     100                                           .05    180   180   150    0                                                   .05    195   195   150    0     100                                           0.1    185   185   150    0                                                   0.1    180   194   150   14     80                                                   180   200         20                                                   .025   200   210    0    10                                                   .025   215   225    0    10                                                   .05    200   220    0    20                                                   .05    215   235    0    20                                                   0.1    210   235    0    25                                                   0.1    215   245    0    30                                      64   2       .025   195   195   30     0                                                   .025   190   190   30     0     100                                           .05    195   195   30     0                                                   .05    190   190   30     0     100                                           0.1    195   195   30     0                                                   0.1    195   195   30     0     100                                           .025   185   185   90     0                                                   .025   185   185   90     0     100                                           .05    190   190   90     0                                                   .05    185   185   90     0     100                                           0.1    190   190   90     0                                                   0.1    190   190   90     0     100                                           .025   190   190   150    0                                                   .025   185   185   150    0     100                                           .05    185   185   150    0                                                   .05    185   185   150    0     100                                           0.1    185   185   150    0                                                   0.1    185   195   150   10     82                                                   185   215         30                                                          180   213         33                                                   .05    220   255    0    35                                                          210   250         40                                                   .1     215   255         40                                                          210   257         47                                      64   5       .05    195   217   30    22     45                                    P.O.*          200   220         20                                                   .1     200   225         25     32                                                   200   235         35                                                   .05    197   215   60    18     50                                                   190   210         20                                                   .1     195   225         30     25                                                   195   230         35                                                   .05    190   200   90    10     61                                                   185   205         20                                                   .1     185   210         25     36                                                   190   220         30                                                   .05    185   205   120   20     47                                                   200   220         20                                                   .1     185   210         25     41                                                   200   227         27                                                   .05    185   195   180   10     49                                                   195   220         25                                                   .1     190   207         17     41                                                   195   230         35                                      64           .05    190   200   240   10     49                                                   195   220         25                                                   .1     190   205         15     48                                                   195   225         30                                                   .025   215   245    0    30                                                   .05    220   255         35                                                   .1     220   255         35                                      66   1       .025   207   225   15    18     40                                            .05    210   225         15     57                                            .1     215   230         15     57                                            .025   205   227   30    27     27                                            .05    215   230         15     57                                            .1     215   235         20     43                                            .025   210   230   60    20     33                                            .05    210   230         20     43                                            .1     210   240         30     14                               66   2       .025   195   205   90    10     67                                            .05    205   220         15     57                                            .1     205   210          5     86                                            .025   200   220   120   20     33                                            .05    200   215         15     57                                            .1     190   205         15     57                                            .025   180   195   150   15     50                                            .05    190   200         10     71                                            .1     185   205         20     43                                            .05    200   255    0    55                                                   .1     200   255         55                                      68   30      .05    180   190   30    10     82                                            .1     180   195         15     73                                            .05    170   185   90    15     73                                            .1     170   175          5     91                                            .05    185   205   150   20     64                                            .1     190   195          5     91                               ______________________________________                                         *oral dosage                                                             

ANTIHYPERTENSIVE EFFECTS IN CONSCIOUS AORTA-COARCTED RENIN/ANGIOTENSINII-DEPENDENT RENAL HYPERTENSIVE RATS

Following the method reported by Chan et al., Drug Development Res.18:75-94,1989, hypertension is induced by complete ligation of the aortabetween the origin of the renal arteries according to the method ofRojo-Ortega and Genest (Can. J. Physio Pharmacol 46: 883-885, 1968.) andFernandes et al., (J. Lab. Clin. Med. 87:561-567, 1976) withmodifications of the surgery procedures. Male Sprague-Dawley rats(Charles River Labs., Inc., Wilmington, Mass.) of 350 to 400 gm bodyweight are anesthetized with methohexital sodium (Brevital sodium, EliLilly and Co.) 60 mg/kg i.p. An incision is made in the left flankparallel to the rib cage. Using No. 3-0 silk suture(Davis & Geck, PearlRiver, N.Y.), the aorta is completely ligated between the origins of therenal arteries. The wound is closed, and the animals returned to theirindividual cages. On the 7th day after aortic coarctation, the rats areused. The rats are restrained in a supine position with elastic tape,and the heads are immobilized by gentle restraining. The ventral portionof the neck is locally anesthetized by subcutaneous infiltration with 2%lidocaine. The left carotid artery is isolated and cannulated with alength of PE50 tubing, which is in turn, connected to a Statham P23Dbpressure transducer --Beckman Dynagraph recording system. In somestudies, the cannular is exteriorized through the back of the neck forlong period of blood pressure monitoring. Recordings are taken over a15-20 minute period, and the rats are dosed with the test compounds orvehicle (saline). After dosing, the blood pressure is monitoredcontinuously. The results are shown in FIGS. 2 to 7.

When the compounds are employed for the above utility, they may becombined with one or more pharmaceutically acceptable carriers, forexample, solvents, diluents and the like, and may be administered orallyin such forms as tablets, capsules, dispersible powders, granules, orsuspensions containing, for example, from about 0.05 to 5% of suspendingagent, syrups containing, for example, from about 10 to 50% of sugar,and elixirs containing, for example, from about 20 to 50% ethanol, andthe like, or parenterally in the form of sterile injectable solutions orsuspension containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 0.05 up to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.5 to about 500 mg/kgof animal body weight, preferably given in divided doses two to fourtimes a day, or in sustained release form. For most large mammals thetotal daily dosage is from about 1 to 100 mg, preferably from about 2 to80 mg. Dosage forms suitable for internal use comprise from about 0.5 to500 mg of the active compound in intimate admixture with a solid orliquid pharmaceutically acceptable carrier. This dosage regimen may beadjusted to provide the optimal therapeutic response. for example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

What is claimed is:
 1. A quinazolinone compound having the formula:##STR40## wherein: R is ##STR41## X is alkyl of 4 carbon atoms; R⁵ is H##STR42## R⁷ and R⁸ are H; and pharmaceutically acceptable saltsthereof.
 2. A pharmaceutical composition useful for treating angiotensininduced hypertension or congestive heart failure in a mammal comprisinga suitable pharmaceutical carrier and an effective amount of a compoundof claim
 1. 3. A method of treating angiotensin induced hypertension ina mammal comprising administering a compound of claim 1 to said mammalan amount effective to lower angiotensin induced hypertension.
 4. Amethod of treating congestive heart failure in a mammal comprisingadministering a compound of claim 1 to said mammal in an amounteffective to treat congestive heart failure.